Headaches: The Common, Challenging Comorbidity

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TALES FROM THE CLINIC

In this installment of Tales From the Clinic: The Art of Psychiatry, we delve into a very common neuropsychiatry comorbidity: headaches. This neuropsychiatric condition is a common comorbidity in a variety of psychiatric diagnoses and can be challenging to manage due to a strong overlap with somatization.

Case Study

“Mr Wright” is a 37-year-old man with no medical comorbidities who has been in the United States for more than 10 years. He presented to primary care with a 4-month history of headaches that were unresponsive to over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs). He is started on amitriptyline 25 mg at bedtime daily and is referred to the psychiatry department for “anxiety” without any further notes on symptoms of anxiety. The patient is worried he will be labeled “crazy” and is upset that his suffering is not being taken seriously.

He appears to be in good physical health with good grooming, although he is somewhat reluctant during the psychiatric interview. He reports that he has been living with his wife and child, and he works at a restaurant. He has teenaged children who do not live with him, but he reportedly has a good relationship with them.

When describing his headaches, Mr Wright relays that they persist all day long and encompass areas around his bilateral temples and occipital area, although the pain may migrate between these areas. He has tried lying down to rest, but the relief in pain is temporary. He is unable to focus on driving and has missed several workdays because he did not feel he could pay attention while driving. He stretches his neck in a variety of different angles during our interaction to help relieve the pain, along with some excess eye blinking that he seems unaware of. He denies a premonitory sensation occurring prior to his movements.

After repeated queries into his stressors around the time his headaches started, Mr Wright is able to verbalize an incident that occurred a week before their onset: He was accommodating his sister at his home after an interpersonal conflict with her husband. The brother-in-law had held him at gunpoint outside his home. He ran inside to safety and the brother-in-law eventually left. His sister has since left, and the patient feels that the turmoil of an abusive relationship in his sister’s life is persistent and acceptable to his sister and the rest of the family. He recalls a similar event more than 20 years ago when he was chased by a different family member in his home country. At that time, Mr Wright also felt that his life was in danger and had to run to safety; since then, he has been an anxious person in general. He has never received any mental health treatment (including psychotherapy).

He denies typical symptoms of posttraumatic stress disorder (PTSD), including nightmares, flashbacks, and avoidance of increased arousal.

A chart review shows that Mr Wright was seen in the emergency department twice since meeting with his primary care provider. On one occasion, he had acute chest pain; negative EKG and cardiac enzymes led to a discharge. On the second occasion, he was evaluated for unprotected sexual contact with an unknown individual. Mr Wright had chosen not to mention either of these instances of his interaction with the medical system, and the psychiatrist chose not to discuss them either.

He was started on amitriptyline 25 mg by his primary care physician 2 weeks ago, and has been using it as needed on nights he is unable to sleep. He finds it useful, but cannot get relief from headaches. He is unable to verbalize any correlation between a life-threatening event and the onset of his headaches.

At the conclusion of the visit, both patient and physician agree that the amitriptyline should be continued, but that the patient should take it more regularly for best therapeutic results.

Discussion

As per a systematic review of a global burden of disease across the United States, in 2017, the 5 highest incidence rates of neurological diseases included migraines and tension-type headaches.¹ Migraines have consistently been among the top 3 neurological diseases in terms of disability-adjusted life years.² As a testament to how frequently psychiatrists and neurologists see patients with headaches and psychiatric diagnoses, in 2019, the most frequent psychiatric comorbidities in individuals with primary headaches in the United States were anxiety and depression, followed by posttraumatic/stressor and trauma-related stress disorder. These comorbidities are found in 25%, 23%, and 15% of the general population, respectively.³

It is inevitable then that one is likely to come across patients with both primary and secondary headaches in psychiatric practice. Recognizing headaches can be a powerful tool in evaluating the quality of life of our patients. Headaches can be triggering and perpetuating factors for psychiatric conditions, in addition to being an important consideration in identifying the best pharmacological options for treatment.

Biopsychosocial Model

In primary headaches such as migraine and tension headaches, there is no source for nociceptive activity such as a hemorrhage or inflammation. Many theories have tried to explain the connections between distress and primary headaches. Findings from studies on connections between distress and primary headaches clearly show that the most important triggering events for primary headaches are distress and sleep issues.⁴ Stress has also been linked with the transformation of episodic migraines to chronic migraines that carry a greater burden of disease.⁵ Interestingly, repeated exposure to trauma, even without a formal PTSD diagnosis, is prominent in adults with chronic migraine headaches as compared with healthy adults without migraines.

Biopsychosocial factors are believed to be involved in headache perception. Transactional models propose that the mismatch between threat perception and capability to deal with the threat can be applied to the subjective sense of pain in migraines, as well as to any other pain syndrome.⁶ Among personality traits, locus of control being perceived as internal versus external is a predictor of better headache outcomes.

During the COVID-19 pandemic, the role of sudden change in psychosocial environment due to shutdowns among those with preexisting migraines has been investigated. Contrary to the impression that headaches would worsen, results from at least 1 study record improvement. The findings document reduction in migraine intensity and frequency in adolescents during the shutdown in Italy in 2020.⁷ It is reasonable to speculate that the reduction in academic and social pressures were helpful in this improvement and underscore the role of psychosocial intervention in patients with migraines. Moreover, it would be interesting to see if there is an uptick in migraine presentation to neurologists and psychiatrists due to the chronic stress induced by the pandemic, over and above migraine in individuals caused by the neuropsychiatric effects of COVID-19 infection itself.

Neuropsychiatry of Headache

Migraine headaches have a bidirectional relationship with a spectrum of psychiatric illnesses, the strongest correlation being with depression, anxiety, and bipolar disorder. There is evidence of shared genetic predisposition, as well as functional and structural alterations in pain-modulating brain areas, including the amygdala, anterior cingulate cortex, and periaqueductal gray in both migraine and affective disorders. Moreover, they share similar abnormalities in the HPA axis as well as common mechanisms of action of treatment modalities.

The concept of central sensitization is often used to explain pain-related conditions, including migraine. Patients with chronic migraines (as compared with episodic migraines) have more somatic complaints. The role of pain sensitization in episodic migraines has also been investigated in episodic migraines. A recent study suggested that slowly repeated evoked pain sensitization could in fact be useful as a clinical predictor for episodic migraines.⁸

Serotonin, norepinephrine, and the GABAergic system have all been implicated in the etiology of psychiatric as well as primary headaches at the neurotransmitters level. As such, the evidence for using serotonin and norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs) that target these receptors for preventive treatment for migraines remains strong.

Pearls in Management

Managing psychiatric symptoms in patients presenting for treatment with headaches may present a unique advantage in overcoming barriers to talking about optimizing mental health. When establishing goals for treatment, it may be useful to educate the patient about the benefit of SNRIs and TCAs in managing headaches as well as mood and anxiety disorders. This may help patients verbalize their mental health needs in the face of stigma. At times, presenting an SNRI or TCA as a headache medicine only can help with treatment adherence in patients who have difficulty expressing their distress.

One of the many challenges in managing headaches is that initiating SNRIs or TCAs for headache can itself carry a risk for inducing headaches. A careful consideration of the timeline for medication-induced headache may aid in separating the superimposed symptoms. Clinicians may benefit from considering medication withdrawal as a reason for headache exacerbation when treating psychiatric patients with comorbid headaches and a history of nonadherence. Venlafaxine is notable in this regard for its withdrawal syndrome.

Investigators of several studies have been unable to establish the benefit of using selective serotonin reuptake inhibitors (SSRIs) in preventing migraine relapses. Among the most studied SSRIs is fluoxetine, which, to date, has conflicting evidence for its use in primary headaches.⁹ Other clinical trials of sertraline and citalopram did not show benefit over TCA or placebo. Hence, when a patient with previously established treatment with SSRIs is placed on TCAs for headaches, one has to carefully weigh the risks and benefits of switching to monotherapy with a TCA or continuing with both medications. If the patient is reporting clinical benefit, they could be treated with low doses of both medication categories while monitoring carefully for adverse effects. Patients can be educated regarding early symptoms of serotonin syndrome when treated in the outpatient setting. 

Additionally, many clinicians are concerned about the possibility of inducing serotonin syndrome in patients taking antidepressants who are prescribed triptans for aborting episodes of migraines. Although there was a black box warning for this interaction, results from an electronic health record–based study in 2018 did not show any correlation of serotonin syndrome with co-use of SSRIs and SNRIs and triptans.¹⁰

In patients with medication-overuse headaches, the prevalence of psychiatric comorbidities is even higher.¹¹ Some point to the similarities between compulsive medication intake for episodes of migraine and obsessive-compulsive disorder. As such, adding behavioral interventions for this subset of patients may be highly effective in improving headache outcomes.

It may be prudent for neurologists to prescribe psychotherapy regularly for treating patients with chronic migraines. Behavioral interventions and forecasting models, including stress variables, seem to be useful in managing migraine. Behavioral treatments with evidence for migraine prevention include stress management, relaxation therapy, cognitive behavioral therapy, biofeedback, mindfulness-based therapies, and acceptance and commitment therapy. Investigators of some studies point out that although headache frequency or intensity improves, there is no change in physiological markers of headaches such as muscle tension. In a landmark study of electromyographic biofeedback training, participants viewed their headaches as having a more internal locus of control and themselves as more self-efficacious (ie, as capable of influencing their headaches) following treatment.¹²

Concluding Thoughts

Finally, when addressing this complex patient population, it is essential to avoid labeling and stigmatization. Patients are usually concerned about physical complaints being dismissed and being told “the symptoms are in your head.” Establishing careful therapeutic rapport goes a long way toward open discussions of treatment options and paving the way to productive illness management.

Dr Shamim is a psychiatrist in Houston, Texas.

References

1. GBD 2017 US Neurological Disorders Collaborators; Feigin VL, Vos T, Alahdab F, et al. Burden of Neurological Disorders Across the US From 1990-2017: A Global Burden of Disease Study. JAMA Neurol. 2021;78(2):165-176.

2. GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396(10258):1204-1222.

3. Caponnetto V, Deodato M, Robotti M, et al; European Headache Federation School of Advanced Studies (EHF-SAS). Comorbidities of primary headache disorders: a literature review with meta-analysis. J Headache Pain. 2021;22(1):71.

4. Yokoyama M, Yokoyama T, Funazu K, et al. Association between headache and stress, alcohol drinking, exercise, sleep, and comorbid health conditions in a Japanese population. J Headache Pain. 2009;10(3):177-185.

5. Xu J, Kong F, Buse DC. Predictors of episodic migraine transformation to chronic migraine: a systematic review and meta-analysis of observational cohort studies. Cephalalgia. 2020;40(5):503-516.

6. Lazarus RS, Folkman S. Stress, Appraisal, and Coping. Springer Publishing Company; 1984.

7. Dallavalle G, Pezzotti E, Provenzi L, et al. Migraine symptoms improvement during the COVID-19 lockdown in a cohort of children and adolescents. Front Neurol. 2020;11:579047.

8. De la Coba P, Bruehl S, Del Paso GAR. Slowly repeated evoked pain (SREP) as a central sensitization marker in episodic migraine patients. Sci Rep. 2021;11(1):4582.

9. Silberstein SD, Holland S, Freitag F, et al; Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1337-1345.

10. Orlova Y, Rizzoli P, Loder E. Association of coprescription of triptan antimigraine drugs and selective serotonin reuptake inhibitor or selective norepinephrine reuptake inhibitor antidepressants with serotonin syndrome. JAMA Neurol. 2018;75(5):566-572.

11. Kristoffersen ES, Straand J, Russell MB, Lundqvist C. Disability, anxiety and depression in patients with medication-overuse headache in primary care – the BIMOH study. Eur J Neurol. 2016;23(suppl 1):28-35.

12. Holroyd KA, Penzien DB, Hursey KG, et al. Change mechanisms in EMG biofeedback training: cognitive changes underlying improvements in tension headache. J Consult Clin Psychol. 1984;52(6):1039-1053.